Combination therapy of metformin plus dipeptidyl peptidase-4 inhibitor versus metformin plus sulfonylurea and their association with a decreased risk of cardiovascular disease in type 2 diabetes mellitus patients

Abstract

Background: Clinical trials assessing the combination therapy of metformin plus dipeptidyl peptidase-4 inhibitors versus metformin plus Sulfonylureas on risk of cardiovascular disease, cardiovascular mortality and/or all-cause mortality in type 2 diabetes have shown conflicting results. We therefore evaluated the combination therapy on the risk of cardiovascular disease, cardiovascular mortality and/or all-cause mortality in type 2 diabetes.

Methods: A systematic search of Medline/PubMed (from 2000 to September 2015), EMBASE (from 2000 to September 2015), and Web of Knowledge (from 2000 to September 2015) for research articles published in English was carried out to examine how combination therapy affects the risk of CVD mortality and/or all-cause mortality in T2DM patients. In addition, the risks of cardiovascular events, CVD mortality, and/or all-cause mortality as well as the adjusted relative risk (RR) or equivalent (hazard ratio or odds ratio) and the corresponding variance or equivalent are reported.

Results: The accumulative RRs (95% confidence intervals) for T2DM patients treated with the combination therapy of metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea were 0.71 (0.56-0.90) for nonfatal cardiovascular events, 1.001 (0.85-1.18) for fatal cardiovascular events, 0.58 (0.41-0.82) for CVD mortality, and 0.72 (0.59-0.87) for all-cause mortality.

Conclusions: The combination therapy of metformin plus DPP-4 inhibitor significantly decreased the RR of nonfatal cardiovascular events, CVD mortality, and all-cause mortality, compared with the combination therapy of metformin plus sulfonylurea. However, the number fatal cardiovascular events (e.g., heart failure) was not significantly different between the 2 groups.

Figure 1

Flow chart summarizing the selection process.

Figure 2

Funnel pool: comparison of metformin plus dipeptidyl peptidase-4 inhibitor versus metformin plus sulfonylurea treatment outcome of a risk of no fatal CVD (A) and all-cause mortality (B) in Type 2 diabetes mellitus patients. CVD = cardiovascular disease.

Figure 3

Forest plot: relative risk (RR) estimates and 95% confidence intervals (CIs) for the nonfatal cardiovascular events (A) and fatal cardiovascular events (B) associated with the combination therapy of metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea by study and pooled along with the proportion of events for each outcome. DPP-4 = dipeptidyl peptidase-4 inhibitors.

Figure 4

Forest plot: relative risk (RR) estimates and 95% confidence intervals (CIs) for the nonfatal cardiovascular events (A) and fatal cardiovascular events (B) associated with the combination therapy of metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea, excluding the study by Ou et al and pooled along with proportion of events for each outcome. DPP-4 = dipeptidyl peptidase-4 inhibitors.

Figure 5

Forest plot: relative risk (RR) estimates and 95% confidence intervals (CIs) for cardiovascular mortality (A) and all-cause mortality (B) associated with the combination therapy of metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea by study and pooled along with proportion of events for each outcome.

Figure 6

Forest plot: relative risk (RR) estimates and 95% confidence intervals (CIs) for cardiovascular mortality associated with the combination therapy of metformin plus DPP-4 inhibitor versus metformin plus sulfonylurea, excluding the study by Kannan et al and pooled along with proportion of events for each outcome. DPP-4 = dipeptidyl peptidase-4 inhibitors.